Using high-resolution chromosomes of bone marrow specimens from 105 consecutive adult patients with de novo acute nonlymphocytic leukemia (ANLL), we have found an unusually high degree of complexity in this disorder, which may explain previous difficulties in finding useful prognostic indicators. Of the 105 patients, 99 were successfully analyzed and 92 (93%) showed a chromosomal defect. Seventeen categories were identified, 12 representing a specific recurrent defect. Such specific defects included 65% of all patients and at least three of them have emerged as having independent prognostic significance. Patients with an inversion 16(9%), diagnosed as either M2, M4, or M5b by the morphological FAB classification, showed a uniform and sustained complete remission and a group median survival of 25 months. In contrast, 14 patients (14%) with complex chromosomal abnormalities and diagnosed variously as M1, M2, M4, M5a, and M6 carried a very poor prognosis. Twelve of the 14 failed to achieve induction remission, and the group had a median survival of 2.5 months. A third group having a trisomy 8 as a single defect (11%) showed an intermediate prognosis with a median survival of 10 months. With the recent availability of different types of treatment for ANLL, we suggest that high-resolution chromosome analysis can become an important tool in selecting specific types of therapy for groups of patients with differing prognoses. Besides chromosome defects of prognostic significance, 16 heritable chromosomal fragile sites (fra) have been defined. Of these, we have found that fra 6p23, 8q22.1, 9p21, 11q13.3, 11q23.3, 12q13.1, 16p12.3, and 16q22.1 are localized at or near the breakpoint of one of the two inversions and six of the 13 specific translocations found in leukemias and non-Hodgkin lymphomas. We have also found a fra 8q22.1 (where the oncogene c-mos has been mapped) in two of two patients with ANLL-M2 and t(8;21)(q22.1;q22.3) in their leukemic marrow cells; a fra 16q22.1 in the normal cells of five of six patients with acute myelomonocytic leukemia and an inv(16)(p13.1q22.1); a fra 11q13.3 (where we have recently mapped the bcl-1 gene) in the normal blood cells of two out of two patients with chronic lymphocytic leukemia and t(11;14)(q13.3;q32.3); and a fra 12q13.1 in a patient with diffuse mixed T-cell lymphoma with t(12;14)(q13.1;q32.3). Confirmation of these findings would suggest that some individuals could be genetically predisposed to develop certain malignancies and a blood test could be developed for screening them. (K)